Exploratory clinical and immunological changes following Tixagevimab/Cilgavimab administration in immunodeficient patients with SARS-CoV-2-associated ME/CFS and persistent circulating spike protein

Background Persistent circulating SARS-CoV-2 spike protein has been proposed as a potential contributor to long-COVID pathophysiology. Whether administration of spike-targeting monoclonal antibodies is followed by changes in spike protein concentrations, autonomic receptor autoantibodies, or clinical outcomes remains uncertain. Methods In this prospective, non-randomized observational study, 21 participants were enrolled. Ten immunodeficient patients with long-COVID-associated ME/CFS and detectable circulating spike protein received Tixagevimab/Cilgavimab for SARS-CoV-2 pre-exposure prophylaxis. One patient subsequently withdrew consent, leaving nine patients for paired baseline and 30-day follow-up analyses. Eleven healthy individuals with previous SARS-CoV-2 infection but without long COVID provided descriptive reference data and were not considered an efficacy control group. Results β1-adrenergic receptor autoantibody concentrations decreased from 26.8 ± 18.2 to 21.2 ± 14.7 U/ml (unadjusted p = 0.003). No statistically significant changes were observed for β2-adrenergic or M3/M4-muscarinic receptor autoantibodies. Median spike protein concentrations changed from 63 pg/ml (IQR 9–127) to 26 pg/ml (IQR 10–120; p = 0.63), with individual decreases observed in five of nine patients. None of the assessed clinical outcomes changed significantly at group level. Changes in spike protein concentrations were not significantly correlated with changes in the assessed autonomic receptor autoantibodies. Conclusion Tixagevimab/Cilgavimab administration was followed by a nominally significant within-patient reduction in β1-adrenergic receptor autoantibody concentrations, but not by conclusive changes in circulating spike protein or clinical outcomes. These findings are preliminary and hypothesis-generating. The small sample size, non-randomized design, brief 30-day follow-up, inclusion of only immunodeficient patients, and absence of an untreated disease-matched control group preclude conclusions regarding therapeutic efficacy.